Ciliary signaling mechanisms regulating white adipose tissue expansion

调节白色脂肪组织扩张的纤毛信号机制

• 批准号: 10503649
• 负责人: Keren Hilgendorf
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-22 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10503649
• 关键词: Ablation; Adipocytes; Adipose tissue; Adult; Affect; Alstrom syndrome; Architecture; Bardet-Biedl Syndrome; Biological; Body mass index; Calories; Cells; Chromatin; Cilia; Cyclic AMP; DNA Sequence Alteration; Data; Defect; Development; Diabetes Mellitus; Docosahexaenoic Acids; Equilibrium; Fatty acid glycerol esters; Female; Functional disorder; Genes; Genetic; Genetic Transcription; Goals; Health; Human; Human Genetics; Hyperplasia; Hypertrophy; Impairment; Inflammation; Insulin Resistance; Lead; Ligands; Link; Metabolic; Metabolic syndrome; Molecular; Monounsaturated Fatty Acids; Morphology; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obese Mice; Obesity; Omega-3 Fatty Acids; Organelles; Overweight; Pathogenesis; Pathogenicity; Patients; Polyunsaturated Fatty Acids; Proteins; Public Health; Publishing; Research; Signal Pathway; Signal Transduction; Techniques; Thinness; Tissue Differentiation; Tissue Expansion; Tissues; chromatin remodeling; ciliopathy; comorbidity; experimental study; glucose metabolism; in vivo; innovation; lipid biosynthesis; lipid metabolism; male; mouse model; novel; pandemic disease; receptor; response; tool; trafficking

Project summary: More than 70% of adults in the USA are obese or overweight, and comorbidities, such as diabetes, pose a significant challenge to public health. In response to excess nutrients, white adipose tissue expands by both hypertrophy and de novo adipogenesis. Excessive hypertrophy is linked to insulin resistance, while mechanisms that promote adipogenesis can limit the pathogenic consequences of obesity. We recently discovered that pre- adipocytes express an antenna-like signaling organelle called the primary cilium, and that primary cilia are required for in vivo adipogenesis. We propose that primary cilia function as signaling hubs in pre-adipocytes, regulating their adipogenic potential, and hence, how white adipose tissue expands in response to caloric imbalance. Remarkably, we recently discovered that pre-adipocytes isolated from obese human and murine white adipose tissue have both fewer and shorter cilia compared to lean pre-adipocytes. To elucidate the functional importance of ciliary signaling in directing how white adipose tissue expands, we propose the following two aims: (Aim 1) Investigate how obesity affects pre-adipocyte ciliation and ciliary signaling. Pre-adipocytes in obese white adipose tissue are known to differentiate poorly due to a cell-intrinsic defect that decreases their adipogenic potential. This contributes to adipocyte hypertrophy, inflammation, and tissue dysfunction. We propose that the obese white adipose tissue microenvironment promotes pathogenic loss of pre-adipocyte primary cilia. This loss results in impairment of ciliary, pro-adipogenic signaling and decreased adipogenic potential, leading to hypertrophic expansion of white adipose tissue and contributing to impairments in glucose and lipid metabolism. Using a combination of molecular and cell biological techniques and mouse models, we will define the adipogenic signaling defects governed by obesity-induced ciliary shortening and loss, as well as the underlying mechanism. (Aim 2) Determine how human genetic mutations in ciliary genes lead to obesity and diabetes. Two ciliopathies are linked to obesity in patients, but the mutations drive opposing effects with regard to metabolic health. Both ciliopathy mutations alter the trafficking of ciliary cargo into and out of the primary cilium. We propose that these alterations modulate the composition of ciliary signaling pathways, altering the adipogenic potential of pre-adipocytes and how white adipose tissue expands. Together, experiments proposed in the two aims will establish the functional importance of pre-adipocyte cilia to white adipose tissue expansion. The proposed research constitutes a completely novel and innovative approach to identifying mechanisms underlying the loss of adipogenic potential of obese pre-adipocytes that drives pathogenesis.

项目概要： 在美国，超过 70% 的成年人肥胖或超重，糖尿病等合并症导致 对公共卫生构成重大挑战。为了应对营养过剩，白色脂肪组织会通过以下两种方式扩张： 肥大和从头脂肪生成。过度肥大与胰岛素抵抗有关，而机制 促进脂肪生成可以限制肥胖的致病后果。我们最近发现预 脂肪细胞表达一种类似天线的信号细胞器，称为初级纤毛，初级纤毛是 体内脂肪生成所需的。我们认为初级纤毛充当前脂肪细胞中的信号中枢， 调节它们的成脂潜力，从而调节白色脂肪组织如何响应热量而扩张 不平衡。值得注意的是，我们最近发现从肥胖的人类和小鼠中分离出前脂肪细胞 与瘦前脂肪细胞相比，白色脂肪组织的纤毛更少且更短。为了阐明 纤毛信号传导在指导白色脂肪组织如何扩张方面的功能重要性，我们提出以下建议 两个目标：（目标 1）研究肥胖如何影响前脂肪细胞纤毛和纤毛信号传导。前脂肪细胞在 众所周知，肥胖的白色脂肪组织由于细胞固有的缺陷而导致其分化能力较差。 成脂潜力。这会导致脂肪细胞肥大、炎症和组织功能障碍。我们 提出肥胖白色脂肪组织微环境促进前脂肪细胞的致病性损失 初级纤毛。这种损失导致纤毛、促脂肪信号传导受损和脂肪形成减少 潜力，导致白色脂肪组织肥大性扩张并导致葡萄糖受损 和脂质代谢。结合分子和细胞生物学技术以及小鼠模型，我们 将定义由肥胖引起的纤毛缩短和损失控制的脂肪形成信号缺陷，以及 底层机制。 （目标 2）确定人类睫状体基因突变如何导致肥胖和肥胖 糖尿病。两种纤毛病与患者的肥胖有关，但这些突变在这方面产生了相反的影响 代谢健康。两种纤毛病突变都会改变纤毛货物进出初级细胞的运输 纤毛。我们认为这些改变调节纤毛信号通路的组成，改变 前脂肪细胞的成脂潜力以及白色脂肪组织如何扩张。一起，提出了实验 这两个目标将确定前脂肪细胞纤毛对白色脂肪组织扩张的功能重要性。 拟议的研究构成了一种完全新颖且创新的机制识别方法 肥胖前脂肪细胞的成脂潜力丧失，从而驱动发病机制。